The present invention relates to novel and useful derivatives of biologically active agents containing a carboxylic acid function.
A wide variety of compounds containing carboxylic acid functions are biologically active. Examples include the non-steroidal anti-inflammatory agents such as naproxen, indomethacin, and voltaren; penicillin and cephalosporin antibiotics such as ampicillin and cefmetazole; herbicides such as Tordon, Endothal, and Amiben; as well as other compounds having biological properties.
The unionized form of a drug is, in general, absorbed more efficiently than its ionic species since the carboxylic acid group is significantly ionized at physiological pH, the result is that agents with carboxylic acid moieties are poorly absorbed through lipid-water membrane barriers. In addition, some acidic drugs, such as the non-steroidal anti-inflammatory agents aspirin, naproxen, ibuprofen, and indomethacin, are irritating to the mucous membrane of the gastrointestinal tract. The general approach to solve these problems has been to esterifying the carboxylic acid function to produce lipophilic and non-irritating prodrug forms, provided that the parent bioactive agent can be released from the esterified form with activity (Design of Prodrugs, H. Bundgaard editor, Elselvier, New York 1985). However, several aliphatic or aromatic esters of carboxylic acid drugs are not sufficiently labile in vivo to ensure a sufficiently high rate and extent of conversion from the esterified form. For example, ethyl esters of naproxen (Harison, I. T. et al. J. Med. Chem., 13, 203, 1970) and fenbufen (Child, R .G. et al. J. Pharm. Sci., 66, 466, 1977) have lower anti-inflammatory activity relative to the free acids which was attributed to the resistance of the esters to be hydrolyzed in vivo.
In contrast, ethyl ester derivatives of angiotensin-converting enzyme inhibitors have improved oral bioavailability. Enalapril is a clinically used ethyl ester prodrug of enalaprillic acid. Plasma enzymes do not hydrolyze the esters and the necessary conversion of the ester to the free acid predominantly takes place in the liver (Tocco, D. J. et al., Drug Metab. Disp. 10, 15, 1982). Accordingly, liver function may be a very important requirement for the bioactivation of enalapril and hence its therapeutic effect. Pentopril is another ethyl ester prodrug of an angiotensin converting enzyme inhibitor which is highly stable in human plasma. Less than 50% of the oral dose of the prodrug ester appears to be hydrolyzed in vivo to the active parent acid (Tipnis, V. and Rakhit A., J. Chromatog. 345, 396, 1985).
Ester derivatives are generally enzymatically cleaved in vivo to release the bioactive parent drug. This may result in a large variation in drug bioavailability, as a function of the variability in enzymatic activity among individuals, or even in the same individual at various times during the day or in various sites where the drug is administered.
It has frequently been found to be desirable to prolong the action of a single dose of some drugs, for example, to prolong the period of activity while the patient is sleeping and to decrease the cost and effort of providing more frequent dosages. In the case of herbicides or pesticides, the longer the agent is available on the site of action the more effective it is. The carboxylic acid forms of these agents are in general hydrophilic and washed out from the site of action shortly after application by rain or irrigation. An hydrophobic water insoluble derivative which degrades slowly to release the active acid form for an extended period of time would increase the efficiency and effectiveness of these compounds.
It is therefore an object of the present invention to provide novel prodrugs characterized by a high susceptibility to undergo hydrolytic degradation and at the same time susceptible to variations in water and lipid solubilities of the derivatives.
It is another object of the present invention to provide prodrugs of compounds having carboxylic acid moieties that slowly degrade by hydrolysis in a designed, predictable and controlled fashion, to a form having the bio-affecting/pharmacological response characteristic of the acids from which they are derived, yet which are characterized in being less irritating to topical and gastric or intestinal mucosal membranes.
It is still another object to the present invention to provide prodrugs of carboxylic acid agents which are more capable of passage through biomembranes so that bioavailability is increased, especially when administered to the gastro-intestinal tract, the rectum, the blood brain barrier, the skin or the eye.
It is a further object of the present invention to provide derivatives of conventional carboxylic acids which are cleaved to release the original drug, while the remaining cleaved moiety is non-toxic and/or is metabolized to nontoxic derivatives.
It is still a further object of the present invention to provide derivatives of bioactive agents for general use such as herbicides, insecticides, fungicides, antimicrobials, pesticides, pheromones, and fertilizers that are more stable and hydrolyze to release the active agent in a controlled manner over an extended period of time, at the site or environment of application.